Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclin
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BioMed Central
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Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer David O Holtz1,2, Robert T Krafty4, Alisha Mohamed-Hadley1, Lin Zhang1, Ioannis Alagkiozidis1, Benjamin Leiby4, Wensheng Guo4,5, Phyllis A Gimotty4,5 and George Coukos*1,2,3 Address: 1Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania, Philadelphia, USA, 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, USA, 3Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, USA, 4Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, USA and 5Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, USA Email: David O Holtz - [email protected]; Robert T Krafty - [email protected]; Alisha Mohamed-Hadley - [email protected]; Lin Zhang - [email protected]; Ioannis Alagkiozidis - [email protected]; Benjamin Leiby - [email protected]; Wensheng Guo - [email protected]; Phyllis A Gimotty - [email protected]; George Coukos* - [email protected] * Corresponding author
Published: 8 January 2008 Journal of Translational Medicine 2008, 6:2
doi:10.1186/1479-5876-6-2
Received: 8 November 2007 Accepted: 8 January 2008
This article is available from: http://www.translational-medicine.com/content/6/1/2 © 2008 Holtz et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials.
Introduction Expansion of vasculature is critical for tumor growth. Tumors cannot grow beyond few millimeters in the absence of angiogenic support provided by vascular endothelial growth factor-A (VEGF-A or VEGF) and other soluble factors
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